This invention is directed to substituted bicyclic compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.
Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix. Many of the cell-cell and cell-extra-cellular matrix interactions are mediated by protein ligands (e.g. fibronectin, VCAM-1 and vitronectin) and their integrin receptors [e.g. xcex15xcex21 (VLA-5), xcex14xcex21 (VLA-4) and xcex1Vxcex23]. Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune disease).
A wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins. Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins. Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X. Cell bound complement C3bi and several transmembrane proteins, such as Ig-like cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), which are members of the Ig superfamily, also serve as cell-surface ligands for some integrins.
Integrins are heterodimeric cell surface receptors consisting of two subunits called xcex1 and xcex2. There are at least fifteen different xcex1-subunits (xcex11-xcex19, xcex1-L, xcex1-M, xcex1-X, xcex1-IIb, xcex1-V and xcex1-E) and at least least seven different xcex2 (xcex21-xcex27) subunits. The integrin family can be subdivided into classes based on the xcex2 subunits, which can be associated with one or more xcex1-subunits. The most widely distributed integrins belong to the xcex21 class, also known as the very late antigens (VLA). The second class of integrins are leukocyte specific receptors and consist of one of three xcex1-subunits (xcex1-L, xcex1-M or xcex1-X) complexed with the xcex22 protein. The cytoadhesins xcex1-IIbxcex23 and xcex1-Vxcex23, constitute the third class of integrins.
The present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor xcex14xcex21 (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.
The integrin xcex14xcex21 mediates both cell-cell and cell-matrix interactions. Cells expressing xcex14xcex21 bind to the carboxy-terminal cell binding domain (CS-1) of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation. The expression of VCAM-1 by endothelial cells is up-regulated by proinflammatory cytokines such as INF-xcex3, TNF-xcex1, IL-1xcex2 and IL-4.
Regulation of xcex14xcex21 mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells. Evidence for the involvement of VLA-4/VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, collitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which xcex14xcex21 binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or VCAM-1 in various in vitro and in vivo experimental models of inflammation. For example, in a Streptococcal cell wall-induced experimental model of arthritis in rats, intravenous administration of CS-1 at the initiation of arthritis suppresses both acute and chronic inflammation (S. M. Wahl et al., J. Clin. Invest., 1994, 94, pages 655-662). In the oxazalone-sensitised model of inflammation (contact hypersensitivity response) in mice, intravenous administration of anti-xcex14 specific monoclonal antibodies significantly inhibited (50-60% reduction in the ear swelling response) the efferent response (P. L. Chisholm et al. J. Immunol., 1993, 23, pages 682-688). In a sheep model of allergic bronchoconstriction, HP1/2, an anti-xcex14 monoclonal antibody given intravenously or by aerosol, blocked the late response and the development of airway hyperresponsiveness (W. M. Abraham et al. J. Clin. Invest., 1994, 93 pages 776-787).
We have now found a novel group of substituted bicyclic compounds which have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (xcex14xcex21).
Thus, in one aspect, the present invention is directed to compounds of general formula (I): 
wherein
Het represents a saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system containing at least one heteroatom selected from O, S or N, optionally substituted by one or more aryl group substituents;
R1 represents optionally substituted aryl or optionally substituted heteroaryl;
R2 represents hydrogen, halogen, lower alkyl or lower alkoxy;
R3 is an alkylene chain, an alkenylene chain or an alkynylene chain;
R4 is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, xe2x80x94C(xe2x95x90Z2)xe2x80x94NR5xe2x80x94, xe2x80x94NR5xe2x80x94C(xe2x95x90Z2)xe2x80x94, xe2x80x94Z2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90NOR5)xe2x80x94, xe2x80x94NR5xe2x80x94, xe2x80x94NR5xe2x80x94C(xe2x95x90Z2)xe2x80x94NR5xe2x80x94, xe2x80x94SO2xe2x80x94NR5xe2x80x94, xe2x80x94NR5xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NR5xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NR5xe2x80x94;
R5 represents hydrogen or lower alkyl;
R6 represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
L1 represents a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage;
L2 represents an alkylene or alkenylene linkage each optionally substituted by R6 or by alkyl substituted by hydroxy, xe2x80x94OR6, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R6 or xe2x80x94NY1Y2;
Y is carboxy or an acid bioisostere;
Y1 and Y2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group xe2x80x94NY1Y2 may form a cyclic amine;
Z1 represents NR5; and
Z2 is O or S;
and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs, but excluding compounds where an oxygen, nitrogen or sulphur atom is attached directly to a carbon-carbon multiple bond of an alkenyl, alkenylene, alkynyl, alkynylene or cycloalkenyl residue.
In the present specification, the term xe2x80x9ccompounds of the inventionxe2x80x9d, and equivalent expressions, are meant to embrace compounds of general formula (I) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAcid bioisosterexe2x80x9d means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21, p283 xe2x80x9cBioisosterism In Drug Designxe2x80x9d; Yun, Hwahak Sekye, 1993,33, p576-579 xe2x80x9cApplication Of Bioisosterism To New Drug Designxe2x80x9d; Zhao, Huaxue Tongbao, 1995, p34-38 xe2x80x9cBioisosteric Replacement And Development Of Lead Compounds In Drug Designxe2x80x9d; Graham, Theochem, 1995,343, p105-109 xe2x80x9cTheoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteresxe2x80x9d). Examples of suitable acid bioisosteres include: xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2OH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2SH, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, heteroarylsulphonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group in which the alkyl group is as described herein.
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain. xe2x80x9cBranchedxe2x80x9d, as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkenylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkenyl group, in which the alkenyl group is as described herein. Exemplary alkenylene radicals include vinylene and propylene.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAlkoxyalkoxyxe2x80x9d means an alkyl-O-alkyl-Oxe2x80x94 group wherein the alkyl groups independently are as defined above. Examples of alkoxyalkoxyl include methoxymethoxy, methoxyethoxy, ethoxyethoxy and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkyl-Oxe2x80x94COxe2x80x94 group in which the alkyl group is as described herein. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAlkylxe2x80x9d means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain optionally substituted by alkoxy or by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. xe2x80x9cLower alkylxe2x80x9d as a group or part of a lower alkoxy, lower alkylthio, lower alkylsulphinyl or lower alkylsulphonyl group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
xe2x80x9cAlkylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkyl group, in which the alkyl group is as described herein. Exemplary alkylene radicals include methylene, ethylene and trimethylene.
xe2x80x9cAlkylenedioxyxe2x80x9d means an xe2x80x94O-alkylene-Oxe2x80x94 group in which alkylene is as defined above. Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
xe2x80x9cAlkylsulphinylxe2x80x9d means an alkyl-SOxe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphinyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylxe2x80x9d means an alkyl-SO2xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphonyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylsulphonylcarbamoylxe2x80x9d means an alkyl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the alkyl group is as previously described. Preferred alkylsulphonylcarbamoyl groups are those in which the alkyl group is C1-4alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (e.g. 2 to 4 carbon atoms) in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
xe2x80x9cAlkynylenexe2x80x9d means an aliphatic bivalent radical derived from a straight or branched alkynyl group, in which the alkynyl group is as described herein. Exemplary alkynylene radicals include ethynylene and propynylene.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as described herein. Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAroylaminoxe2x80x9d is an aroyl-NHxe2x80x94 group wherein aroyl is as previously defined.
xe2x80x9cArylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulphinyl, alkylsulphonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulphinyl, arylsulphonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y1Y2Nxe2x80x94, Y1Y2NCOxe2x80x94, Y1Y2NSO2xe2x80x94, Y1Y2Nxe2x80x94C2-6alkylene-Z1xe2x80x94, alkylC(xe2x95x90O)-Y1Nxe2x80x94, alkylSO2xe2x80x94Y1Nxe2x80x94 or alkyl optionally substituted with aryl, heteroaryl, hydroxy, or Y1Y2Nxe2x80x94. When R1 is an optionally substituted aryl group, this may particularly represent optionally substituted phenyl.
xe2x80x9cArylalkenylxe2x80x9d means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred arylalkenyls contain a lower alkenyl moiety. Exemplary arylalkenyl groups include styryl and phenylallyl.
xe2x80x9cArylalkylxe2x80x9d means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cArylalkyloxyxe2x80x9d means an arylalkyl-Oxe2x80x94 group in which the arylalkyl groups is as previously described. Exemplary arylalkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy.
xe2x80x9cArylalkyloxycarbonylxe2x80x9d means an arylalkyl-Oxe2x80x94COxe2x80x94 group in which the arylalkyl groups is as previously described. An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cArylalkylthioxe2x80x9d means an arylalkylxe2x80x94Sxe2x80x94 group in which the arylalkyl group is as previously described. An exemplary arylalkylthio group is benzylthio.
xe2x80x9cArylalkynylxe2x80x9d means an aryl-alkynyl- group in which the aryl and alkynyl are as previously described. Exemplary arylalkynyl groups include phenylethynyl and 3-phenylbut-2-ynyl.
xe2x80x9cArylenexe2x80x9d means an optionally substituted bivalent radical derived from an aryl group. Exemplary arylene groups include optionally substituted phenylene, naphthylene and indanylene. Suitable substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above, particularly halogen, methyl or methoxy.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
xe2x80x9cArylsulphinylxe2x80x9d means an aryl-SOxe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylxe2x80x9d means an aryl-SO2xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylsulphonylcarbamoylxe2x80x9d means an aryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the aryl group is as previously described.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cCyclic aminexe2x80x9d means a 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen and which (i) may optionally contain an additional heteroatom selected from O, S or NY3 (where Y3 is hydrogen, alkyl, arylalkyl, and aryl) and (ii) may be fused to additional aryl or heteroaryl ring to form a bicyclic ring system. Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline and pyrindoline.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
xe2x80x9cCycloalkenylalkylxe2x80x9d means a cycloalkenyl-alkyl- group in which the cycloalkenyl and alkyl moieties are as previously described. Exemplary cycloalkenylalkyl groups include cyclopentenylmethyl, cyclohexenylmethyl or cycloheptenylmethyl.
xe2x80x9cCycloalkenylenexe2x80x9d means a bivalent radical derived from an unsaturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopentenylene and cyclohexenylene.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms optionally substituted by oxo. Exemplary monocyclic cycloalkyl rings include C3-8cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
xe2x80x9cCycloalkylalkylxe2x80x9d means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
xe2x80x9cCycloalkylenexe2x80x9d means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring. Exemplary cycloalkenylene radicals include cyclopentylene and cyclohexylene.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
xe2x80x9cHeteroaroylxe2x80x9d means a heteroaryl-C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as described herein. Exemplary groups include pyridylcarbonyl.
xe2x80x9cHeteroaroylaminoxe2x80x9d means a heteroaroyl-NHxe2x80x94 group in which the heteroaryl moiety are as previously described.
xe2x80x9cHeteroarylxe2x80x9d as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents as defined above); (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which a heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups). Optional substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above.
xe2x80x9cHeteroarylalkenylxe2x80x9d means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as previously described. Preferred heteroarylalkenyl groups contain a lower alkenyl moiety. Exemplary heteroarylalkenyl groups include pyridylethenyl and pyridylallyl.
xe2x80x9cHeteroarylalkylxe2x80x9d means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C1-4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
xe2x80x9cHeteroarylalkyloxyxe2x80x9d means an heteroarylalkyl-Oxe2x80x94 group in which the heteroarylalkyl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
xe2x80x9cHeteroarylalkynylxe2x80x9d means a heteroaryl-alkynyl- group in which the heteroaryl and alkynyl moieties are as previously described. Exemplary heteroarylalkenyl groups include pyridylethynyl and 3-pyridylbut-2-ynyl.
xe2x80x9cHeteroaryldiylxe2x80x9d means a bivalent radical derived from an aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur, and optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above.
xe2x80x9cHeteroaryloxyxe2x80x9d means an heteroaryl-Oxe2x80x94 group in which the heteroaryl group is as previously described. Exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
xe2x80x9cHeteroarylsulphonylcarbamoylxe2x80x9d means a heteroaryl-SO2xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94 group in which the heteroaryl group is as previously described.
xe2x80x9cHeterocyclexe2x80x9d denotes an optionally substituted saturated, partially saturated or fully unsaturated monocyclic organic moiety of 5 or 6 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur. Exemplary 5 or 6 membered heterocycles include furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, oxazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups. Optional substituents include one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above.
xe2x80x9cHeterocycloalkylxe2x80x9d means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms selected from O, S or NY3; (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl ring) and a heterocycloalkyl group are fused together to form a cyclic structure (examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).
xe2x80x9cHeterocycloalkylalkylxe2x80x9d means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
xe2x80x9cHeterocycloalkylenexe2x80x9d means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 5 to about 7 atoms, which contains one or more heteroatoms selected from O, S or NY4 (where Y4 is hydrogen, alkyl, arylalkyl, and aryl) and is optionally substituted by oxo, by removing a hydrogen atom from each of two different carbon atoms of the ring, or when NY4 is NH by removing a hydrogen atom from one carbon atom of the ring and a hydrogen atom from the NH, or when the ring contains two NY4 heteroatoms and NY4 is NH by removing a hydrogen atom from both nitrogen atoms.
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof. For example an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
Suitable esters of compounds of formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-xcex2-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
Suitable esters of compounds of formula (I) containing a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379.
Suitable esters of compounds of formula (I) containing both a carboxy group and a hydroxy group within the moiety xe2x80x94L2xe2x80x94Y, include lactones, formed by loss of water between said carboxy and hydroxy groups. Examples of lactones include caprolactones and butyrolactones.
An especially useful class of esters of compounds of formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1 -yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
Where the compound of the invention contains a carboxy group, or a sufficiently acidic bioisostere, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g. hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
With reference to formula (I) above, the following are particular and preferred groupings:
R1 may particularly represent optionally substituted aryl, especially optionally substituted phenyl.
Z1 may particularly represent NH.
Het may particularly represent 
wherein ring 
is a 5 or 6 membered heterocycle and ring 
is a 5 or 6 membered fully unsaturated heterocycle or a benzene ring, each ring optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above, and the two rings are joined together by a carbon-carbon linkage or a carbon-nitrogen linkage.
Ring 
may particularly represent a 5 membered fully unsaturated heterocycle.
Ring 
may particularly represent a benzene ring, optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above. 
may particularly represent a 9 membered bicyclic system in which rings 
are as defined just above and the two rings are joined together by carbon atom linkages. 
is preferably benzoxazolyl or benzimidazolyl, in which ring 
is optionally substituted by one or more xe2x80x9caryl group substituentsxe2x80x9d as defined above [examples of particular aryl group substituents include C1-4 alkyl (e.g. methyl or ethyl), C 1-4 alkoxy (e.g. methoxy), amino, halogen, hydroxy, C1-4 alkylthio, C1-4 alkylsulphinyl, C1-4 alkylsulphonyl, nitro or trifluoromethyl].
L1 may particularly represent a xe2x80x94R3xe2x80x94R4-linkage where R3 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, and R4 represents xe2x80x94C(xe2x95x90Z2)xe2x80x94NR5xe2x80x94, preferably xe2x80x94C(xe2x95x90O)xe2x80x94NR5xe2x80x94, especially where R5 is hydrogen or C1-4 alkyl, more especially hydrogen.
R2 may particularly represent hydrogen.
L2 may particularly represent an optionally substituted alkylene linkage, especially optionally substituted ethylene. Preferred optional substituents include C1-4 alkyl (e.g. methyl), aryl (e.g. optionally substituted phenyl), or alkyl substituted by hydroxy, xe2x80x94OR6, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R6 or xe2x80x94NY1Y2. L2 is preferably a group 
where R7 is hydrogen or C1-4 alkyl (e.g. methyl) and R8 represents hydrogen or C1-4 alkyl (e.g. methyl), or where R7 is hydrogen and R8 represents aryl (e.g. optionally substituted phenyl) or alkyl substituted by hydroxy, xe2x80x94OR4, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R6 or xe2x80x94NY1Y2. L2 is more preferably a group 
where R8 represents C1-4 alkyl (e.g. methyl), aryl (e.g. optionally substituted phenyl), or alkyl substituted by hydroxy, xe2x80x94OR6, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R6 or xe2x80x94NY1Y2.
Y may particularly represent carboxy.
It is to be understood that this invention covers all appropriate combinations of the particular and preferred groupings referred to herein.
A particular group of compounds of the invention are compounds of formula (Ia): 
in which R1, R2, R3, R5, L2, Y and Z1 are as hereinbefore defined, R13 is hydrogen or an aryl group substituent and X is O or NR9 (in which R9 is hydrogen or C1-4 alkyl), and their prodrugs and pharmaceutically acceptable salts, and solvates (e.g. hydrates) of compounds of formula (Ia) and their prodrugs.
Compounds of formula (Ia) in which R1 represents optionally substituted aryl, especially optionally substituted phenyl, are preferred. Preferred optional substituents include C1-4 alkyl (e.g. methyl), C1-4 alkyl (e.g. methoxy), halo (e.g. fluoro) and Y1Y2Nxe2x80x94 (e.g. dimethylamino). R1 especially represents ortho-tolyl.
Compounds of formula (Ia) in which Z1 represents NH are preferred.
Compounds of formula (Ia) in which R13 represents hydrogen, C1-4 alkyl (e.g. methyl or ethyl) or C1-4 alkoxy (e.g. methoxy) are preferred.
Compounds of formula (Ia) in which R3 represents a straight or branched C1-6alkylene chain, especially a straight or branched C1-4alkylene chain, more especially methylene, are preferred.
Compounds of formula (Ia) in which R5 represents hydrogen are preferred.
Compounds of formula (Ia) in which R2 represents hydrogen are preferred.
Compounds of formula (Ia) in which L2 represents an optionally substituted alkylene linkage, especially ethylene or substituted ethylene, are preferred. Preferred optional substituents include C1-4 alkyl (e.g. methyl), aryl (e.g. optionally substituted phenyl) or alkyl substituted by hydroxy, xe2x80x94OR6, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R6 or xe2x80x94NY1Y2. Compounds of formula (Ia) in which L2 is a 
linkage, where
R7 is hydrogen or C1-4 alkyl (e.g. methyl) and R8 represents hydrogen or C1-4 alkyl (e.g. methyl), or where R7 is hydrogen and R8 represents aryl (e.g. optionally substituted phenyl) or alkyl substituted by hydroxy, xe2x80x94OR6, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R6 or xe2x80x94NY1Y2 are particularly preferred. Compounds of formula (Ia) in which L2 is a 
linkage, where R8 represents C1-4 alkyl (e.g. methyl), aryl (e.g. optionally substituted phenyl), or alkyl substituted hydroxy, xe2x80x94OR6, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R6 or xe2x80x94NY1Y2, are especially preferred.
Compounds of formula (Ia) in which Y represents carboxy are preferred.
The group 
may preferably be attached at the ring 6 position when X is O or NH, or at the ring 5 or 6 position when X is NR9 and R9 is C1-4 alkyl.
The group xe2x80x94L2xe2x80x94Y may preferably be attached at the 4xe2x80x2 position of the phenyl ring.
A preferred group of compounds of the invention are compounds of formula (Ia) in which: R1 is optionally substituted phenyl (especially C1-4 alkyl substituted phenyl, more especially ortho-tolyl); Z1 is NH; X is O; R13 represents hydrogen, C1-4 alkyl (e.g. methyl or ethyl) or C1-4alkoxy (e.g. methoxy); R3 is a straight or branched C1-4alkylene chain, (especially methylene); R5 is hydrogen; R2 is hydrogen; L2 is a 
group or preferably a 
group, where R8 represents hydrogen, C1-4 alkyl (especially methyl), aryl (e.g. optionally substituted phenyl) or alkyl substituted by hydroxy, xe2x80x94OR6, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R6 or xe2x80x94NY1Y2; Y is carboxy; the group 
is attached at the ring 6 position; and the group xe2x80x94L2xe2x80x94Y is attached at the 4xe2x80x2 position of the phenyl ring; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Another preferred group of compounds of the invention are compounds of formula (la) in which: R1 is optionally substituted phenyl (especially C1-4 alkyl substituted phenyl, more especially ortho-tolyl);
Z1 is NH; X is NR9 (especially NH); R13 represents hydrogen, C1-4 alkyl (e.g. methyl or ethyl) or
C1-4 alkoxy (e.g. methoxy); R3 is a straight or branched C1-4alkylene chain, (especially methylene);
R5 is hydrogen; R2 is hydrogen; L2 is a 
group or preferably a 
group, where R8 represents hydrogen, C1-4 alkyl (especially methyl), aryl (e.g. optionally substituted phenyl) or alkyl substituted by hydroxy, xe2x80x94OR6, xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94R6 or xe2x80x94NY1Y2; Y is carboxy; the group 
is attached at the ring 5 or 6 position; and the group xe2x80x94L2xe2x80x94Y is attached at the 4xe2x80x2 position of the phenyl ring; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
Particular compounds of the invention are selected from the compounds formed by joining the acyl carbon atom (C*) of one of the fragments (A1 to A36) shown in Table 1 to the nitrogen atom (N*) of one of the fragments (B1 to B4) shown in Table 2, and joining the carbon atom (C*) of the phenyl ring in one of the fragments (B1 to B4) shown in Table 2 to the carbon atom (C*) of one of the acidic fragments (C1 to C27) depicted in Table 3.
Particularly preferred examples of fragments xe2x80x9cAxe2x80x9d, xe2x80x9cBxe2x80x9d, and xe2x80x9cCxe2x80x9d are illustrated below:
Thus, for example, in the above list the compound denoted as A1-B1-C1 is the product of the combination of group A1 in Table 1 and B1 in Table 2 and C1 in Table 3, namely 
Preferred compounds of the invention are:
R) 3-{4-[2-(4-methoxy-2-o-tolylaminobenzoxazol-6-yl)acetylamino]phenyl}butanoic acid;
(R) 3-{4-[2-(4-methyl-2-o-tolylaminobenzoxazol-6-yl)acetylamino]phenyl}-butanoic acid;
(R,S) 3-phenyl-3-[4-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl]-propanoic acid; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds and their N-oxides and prodrugs.
The compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
Compounds within the scope of the present invention block the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21) according to tests described in the literature and described in vitro and in vivo procedures hereinafter, and which tests results are believed to correlate to pharmacological activity in humans and other mammals. Thus, in a further embodiment, the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of xcex14xcex21 mediated cell adhesion. For example, compounds of the present invention are useful in the treatment of inflammatory diseases, for example joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. Additionally, the compounds are useful in the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis restenosis, myocarditis, inflammatory bowel disease and melanoma cell division in metastasis.
A special embodiment of the therapeutic methods of the present invention is the treating of asthma.
Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
According to a further feature of the invention there is provided a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), for example conditions as hereinbefore described, which comprises the administration to the patient of an effective amount of compound of the invention or a composition containing a compound of the invention. xe2x80x9cEffective amountxe2x80x9d is meant to describe an amount of compound of the present invention effective in inhibiting the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (xcex14xcex21), and thus producing the desired therapeutic effect.
References herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions.
The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
Compounds of the invention may be administered by any suitable means. In practice compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
Compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations. The choice of vehicle and the content of active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions to be observed m pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets. To prepare a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, emulsions, suspensions or solutions of the products according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. The aqueous solutions, also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
For topical administration, gels (water or alcohol based), creams or ointments containing compounds of the invention may be used. Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
For administration by inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
The compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d John Wiley and Sons, 1991.
Compounds of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined, and Y is carboxy may be prepared by hydrolysis of esters of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined and where the Y is a xe2x80x94CO2R10 group (in which R10 is alkyl, alkenyl or arylalkyl). The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50xc2x0 C. to about 80xc2x0 C.
As another example compounds of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined, and Y is carboxy may be prepared by acid catalysed removal of the tert-butyl group of tert-butyl esters of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined and Y is a xe2x80x94CO2R10 group (in which R10 is tert-butyl), using standard reaction conditions, for example reaction with trifluoroacetic acid at a temperature at about room temperature.
As another example compounds of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined and Y is carboxy may be prepared by hydrogenation of compounds of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined and Y is a xe2x80x94CO2R10 group (in which R10 is benzyl). The reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, e.g. palladium, supported on an inert carrier such as carbon, preferably in a solvent such as B methanol or ethanol and at a temperature at about reflux temperature. The reaction may alternatively be carried out in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage (in which R3 is as hereinbefore defined and R4 is xe2x80x94C(xe2x95x90O)xe2x80x94NR5xe2x80x94) and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be prepared by reaction of compounds of formula (II):
R1Z1xe2x80x94Hetxe2x80x94R3xe2x80x94C(xe2x95x90O)xe2x80x94X1xe2x80x83xe2x80x83(II)
wherein Het, R1, R3 and Z1 are as hereinbefore and X1 is a hydroxy group or a halogen, preferably chlorine, atom, with amines of formula (III): 
wherein R2, R5, R10 and L2 are as hereinbefore defined. When X1 is a hydroxy group the reaction may be carried out using standard peptide coupling procedures for example coupling in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide), at room temperature. When X1 is a halogen atom the acylation reaction may be carried out with the aid of a base, such pyridine, preferably in a solvent such as tetrahydrofuran and at a temperature at about room temperature.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage [in which R3 is as hereinbefore defined, and R4 is xe2x80x94NR5xe2x80x94C(xe2x95x90O)xe2x80x94 (where R5 is as hereinbefore defined)] and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be prepared by reaction of compounds of formula (IV):
R1Z1xe2x80x94Hetxe2x80x94R3xe2x80x94NHR5xe2x80x83xe2x80x83(IV)
wherein Het, R1, R3, R5 and Z1 are as hereinbefore, with compounds of formula (V): 
wherein R2, R10 and L2 are as hereinbefore defined and X2 is a hydroxy group or a halogen, preferably chlorine, atom, using procedures described hereinbefore for coupling acids or acid halides with amines.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94linkage (in which R3 is as hereinbefore defined and R4 is xe2x80x94Oxe2x80x94) and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be prepared by reaction of compounds of formula (VI):
R1Z1xe2x80x94Hetxe2x80x94R3xe2x80x94OHxe2x80x83xe2x80x83(VI)
wherein Het, R1, R3 and Z1 are as hereinbefore defined with compounds of formula (VII): 
wherein R2, R10 and L2 are as hereinbefore defined and Z2 is O, in the presence of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate, and triphenylphosphine, preferably in a dry ethereal solvent, e.g. diethyl ether or tetrahydrofuran, preferably at or near room temperature.
Alternatively esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage (in which R3 is as hereinbefore defined and R4 is xe2x80x94Oxe2x80x94) and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be prepared by alkylation of compounds of formula (VII), wherein R2, R10 and L2 are as hereinbefore defined and Z2 is O with the appropriate alkyl bromides of formula (VII):
R1Z1xe2x80x94Hetxe2x80x94R3xe2x80x94X3xe2x80x83xe2x80x83(VIII)
Het, R1, R3 and Z1 are as hereinbefore defined and X3 is a halogen, preferably bromo, atom using standard alkylation conditions. The alkylation may for example be carried out in the presence of a base, such as an alkali metal carbonate, e.g. potassium carbonate, or alkali metal hydride, e.g. sodium hydride, in dimethylformamide, or dimethyl sulphoxide, at a temperature from about 0xc2x0 C. to about 100xc2x0 C.
Esters of formula (I) wherein R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage (in which R3 is as hereinbefore defined and R4 is xe2x80x94Sxe2x80x94) and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be similarly prepared by alkylation-n of compounds of formula (VII) wherein R2, R10 and L2 are as hereinbefore defined and Z2 is S.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage [in which R3 is as hereinbefore defined and R4 is xe2x80x94NR5xe2x80x94 (where R5 is as hereinbefore defined)] and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be similarly prepared by alkylation of compounds of formula (III), wherein R2, R5, R10 and L2 are as hereinbefore defined.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage [in which R3 is as hereinbefore defined and R4 is xe2x80x94C(xe2x95x90O)xe2x80x94] and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be prepared by reaction of esters of formula (IX):
R1Z1xe2x80x94Hetxe2x80x94R3xe2x80x94CO2R10xe2x80x83xe2x80x83(IX)
wherein Het, R1, R3 and Z1 are as hereinbefore defined and R10 is lower alkyl, with Grignard reagents derived from reaction of compounds of formula (X): 
wherein R2 and L2 are as hereinbefore defined and X4 is a suitably protected carboxylic acid group, with magnesium using standard reaction conditions, followed by removal of the carboxylic acid protecting group.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage [in which R3 is as hereinbefore defined and R4 is xe2x80x94NR5xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 (where R5 is as hereinbefore defined)] and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be prepared by reaction of compounds of formula (IV) wherein Het, R1, R3, R5 and Z1 are as hereinbefore defined, with isocyanates of formula (XI): 
wherein R2, R10 and L2 are as hereinbefore defined. The reaction is preferably carried out with the aid of a base, such as a tertiary amine, for example triethylamine, preferably in a solvent such as dichloromethane, and at a temperature at about room temperature.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage [in which R3 is as hereinbefore defined and R4 is xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NR5xe2x80x94 (where R5 is as hereinbefore defined)] and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be similarly prepared by reaction of amines of formula (III) wherein R2, R5, R10 and L2 are as hereinbefore defined with compounds of formula (XII):
R1Z1xe2x80x94Hetxe2x80x94R3xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(XII)
wherein Het, R1, R3 and Z1 are as hereinbefore defined.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage [in which R3 is as hereinbefore defined and R4 is xe2x80x94SO2xe2x80x94NR5xe2x80x94 (where R5 is as hereinbefore defined)] and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be prepared by reaction of compounds of formula (XIII):
R1Z1xe2x80x94Hetxe2x80x94R3xe2x80x94SO2Clxe2x80x83xe2x80x83(XIII)
wherein Het, R1, R3 and Z1 are as hereinbefore defined, with amines of formula (III) wherein R2, R5, R10 and L2 are as hereinbefore defined. The reaction is preferably carried out with the aid of a base, such as a tertiary amine, for example triethylamine, preferably in a solvent such as tetrahydrofuran and at a temperature at about room temperature.
Esters of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage [in which R3 is as hereinbefore defined and R4 is xe2x80x94NR5xe2x80x94SO2xe2x80x94 (where R5 is as hereinbefore defined)] and Y is a xe2x80x94CO2R10 group (in which R10 is as hereinbefore defined) may be similarly prepared by reaction of compounds of formula (IV) wherein Het, R1, R3, R5 and Z1 are as hereinbefore defined with sulphonyl chlorides of formula (XIV): 
wherein R2, R10 and L2 are as hereinbefore defined.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage [in which R3 is as hereinbefore defined and R4 is xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94] and Y is a xe2x80x94CO2R10 group (where R10 is as hereinbefore defined) may be prepared by O-acylation of compounds of formula (VI) wherein Het, R1, R3, and Z1 are as hereinbefore defined with compounds of formula (V) wherein R2, R10 and L2 are as hereinbefore defined and X2 is a chlorine atom. The reaction may be carried using standard O-acylation conditions, for example reaction in the presence of a base, such as triethylamine or pyridine, at a temperature from about 0xc2x0 C. to about room temperature.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage [in which R3 is as hereinbefore defined and R4 is xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94] and Y is a xe2x80x94CO2R10 group (where R10 is as hereinbefore defined) may be similarly prepared by O-acylation of compounds of formula (VII) wherein R2, R10 and L2 are as hereinbefore defined and Z2 is O with compounds of formula (II) wherein Het, R1, R3 and Z1 are as hereinbefore defined and X1 is a chlorine atom.
Esters of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage (in which R3 is as hereinbefore defined and R4 is xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94) and Y is a xe2x80x94CO2R10 group (where R10 is as hereinbefore defined) may be prepared by reaction of compounds of formula (VI) wherein Het, R1, R3 and Z1 are as hereinbefore defined with isocyanates of formula (XI) wherein R2, R10 and L2 are as hereinbefore defined The reaction is preferably carried out with the aid of a base, such as a tertiary amine, for example triethylamine, preferably in a solvent such as dichloromethane, and at a temperature at about room temperature.
Esters of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage (in which R3 is as hereinbefore defined and R4 is xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94] and Y is a xe2x80x94CO2R10 group (where R10 is as hereinbefore defined) may be similarly prepared by reaction of isocyanates of formula (XII) wherein Het, R1, R3 and Z1 are as hereinbefore defined with compounds of formula (VII) wherein R2, R10 and L2 are as hereinbefore defined and Z2 is O.
Esters of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage (in which R3 is a direct bond and R4 is a straight or branched chain C2-6alkenylene chain where the carbon-carbon double bond is directly attached to the phenyl ring containing the xe2x80x94L2xe2x80x94Y group) may be prepared by reaction of compounds of formula (XV): 
wherein R2, R10 and L2 are as hereinbefore defined, with an appropriate phosphorane (or phosphonate ester) of formula (XVI):
R1Z1xe2x80x94Hetxe2x80x94R3xe2x80x94X5xe2x80x83xe2x80x83(XVI)
wherein Het, R1 and Z1 are as hereinbefore defined, R3 is a straight or branched chain C1-5alkylene chain and X5 is xe2x95x90PPh3+Brxe2x88x92 (or xe2x80x94P(xe2x95x90O)(OEt)2), using standard Wittig (or Horner-Wadsworth-Emmons) coupling procedures (for example those described in Tetrahedron Organic Chemistry Series Volume 11, Organic Synthesis Based On Name Reactions and Unnamed reactions, Editors, J. E. Balwin and P. D. Magnus, pages 181 and 421).
Lactones of formula (I) wherein Het, R1, R2, L1 and Z1 are as hereinbefore defined and the moiety xe2x80x94L2xe2x80x94Y is 
may be prepared by the selective reduction (using for example a borane derivative or lithium borohydride) of compounds of formula (I) wherein Het, R1, R2, L1 and Z1 are as hereinbefore defined and the moiety xe2x80x94L2xe2x80x94Y is 
in which R11 is lower alkyl, followed by spontaneous cyclisation of the intermediate hydroxy compound. The reduction can be achieved by the application or adaptation of the procedures described by C. J. Francis and J. Bryan Jones, J. Chem. Soc, Chem. Commun., 1984, (9), 579-58, J. Hiratake et al, J. Chem. Soc, Perkin Trans, 1987,1 (5), 1053-8 or L. K. P. Lam et al, J. Org. Chem. (1986), 51(11), 2047-50.
Lactones of formula (I) wherein Het, R1, R2, L1 and Z1 are as hereinbefore defined and the moiety xe2x80x94L2xe2x80x94Y is 
may be similarly prepared from compounds of formula (I) wherein Het, R1,
R2, L1 and Z1 are as hereinbefore defined and the moiety xe2x80x94L2xe2x80x94Y is 
in which R11 is lower alkyl.
Lactones of formula (I) wherein Het, R1, R2, L1 and Z1 are as hereinbefore defined and the moiety xe2x80x94L2xe2x80x94Y is 
may be similarly prepared from compounds of formula (I) wherein Het, R1, R2, L1 and Z1 are as hereinbefore defined and the moiety xe2x80x94L2xe2x80x94Y is 
in which R11 is lower alkyl.
Compounds of formula (I) wherein Het, R1, R2, L2 and Z1 are as hereinbefore defined, and Y is carboxy, represented by formula (XVII), may be prepared using resin technology as shown in scheme 1.
For example Wang resin, 4-hydroxymethylphenoxylated styrene/divinylbenzene copolymer, where 
represents the polymeric core (comprising polystyrene crosslinked with 1% to 2% divinylbenzene), may be treated, in Step 1, with acids of formula (XVIII): 
wherein R2 and L2 are as hereinbefore defined, with diisopropyl carbodiimide in dimethylformamide, in the presence of dimethylaminopyridine, at room temperature. The resulting esters (Resin 1), wherein R2, L2 and 
are as hereinbefore defined, may then treated, in Step 2, with tin chloride in dimethylformamide at room temperature to give Resin 2, wherein R2, L2 and 
are as hereinbefore defined. Resin 2 may then be coupled, in Step 3, with acids of general formula (II) wherein Het, R1, R3 and Z1 are as hereinbefore and X1 is hydroxy, in the presence of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, at room temperature. The resulting Resin 3, wherein Het, R1, R2, R3, L2, Z1 and R2, L2 and 
are as hereinbefore defined, may then be treated, in Step 4, with trifluoroacetic acid in an inert solvent such as dichloromethane, at room temperature, to liberate the acids of general formula (XVII), wherein Het, R1, R2, R3, L2 and Z1 are as hereinbefore defined.
Compounds of formula (Ia) wherein R1, R2, R3, R13 and L2 are as hereinbefore defined, R5 is hydrogen, X is O, Z1 is NH and Y is carboxy, represented by formula (XVIIa), may be prepared using resin technology as shown in scheme 2.
For example Resin 2 may be coupled, in Step 1, with acids of general formula (XXI) wherein R3 and R13 are as hereinbefore and X is O, in the presence of O-(7-azabenzotriazo-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, at room temperature to give Resin 4 wherein R2, R3, L2 and 
are as hereinbefore defined. Resin 4 may then be treated with tin chloride in dimethylformamide at room temperature followed treatment with isocyanates of formula R1xe2x80x94Nxe2x95x90Cxe2x95x90O in dimethylformamide at room temperature and then treatment with diisopropylcarbodimide in dimethylformamide at 75xc2x0 C. The resulting Resin 5, wherein R1, R2, R3, L2 and 
are as hereinbefore defined, may then be treated, in Step 3, with trifluoroacetic acid in an inert solvent such as dichloromethane, at room temperature, to liberate the acids of general formula (XVIIa), wherein R1, R2, R3 and L2 are as hereinbefore defined.
According to a further feature of the present invention, compounds of the invention may be prepared by interconversion of other compounds of the invention.
For example compounds of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined and Y is xe2x80x94C(xe2x95x90O)xe2x80x94NHOH, may be prepared by reaction of compounds of formula (I) wherein Het, R1, R2, L1, L2 and Z1 are as hereinbefore defined and Y is carboxy, with hydroxylamine using standard peptide coupling procedures such as treatment with a carbodiimide, for example dicyclohexylcarbodiimide, in the presence of triethylamine, in an inert solvent such as dichloromethane or tetrahydrofuran and at a temperature at about room temperature. The coupling may also be carried out using 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in dichloromethane at room temperature. The preparation may also be carried out using an O-protected hydroxylamine such as O-(trimethylsilyl)hydroxylamine, O-(t-butyldimethylsilyl)-hydroxylamine, or O-(tetrahydropyranyl)hydroxylamine followed by treatment with acid.
As another example of the interconversion process, compounds of formula (J) wherein Het, R1, R2, L1, Z1 and Y are as hereinbefore defined and L2 is an optionally substituted alkylene linkage, may be prepared by hydrogenation of the corresponding compounds of formula (I) in which L2 is the corresponding optionally substituted alkenylene linkage. The hydrogenation may be carried out using hydrogen (optionally under pressure) in the presence of a suitable metal catalyst, e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol, and at a temperature at about room temperature.
As another example of the interconversion process, compounds of formula (I) wherein Het, R1, R2, L2, Z1 and Y are as hereinbefore described and L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage where R3 is a straight or branched chain C2-6alkylene chain and R4 is a direct bond, may be similarly prepared by hydrogenation of the corresponding compounds of formula (I) in which L1 is a xe2x80x94R3xe2x80x94R4xe2x80x94 linkage where R3 is a straight or branched chain C2-6alkenylene chain and R4 is a direct bond.
As another example of the interconversion process, compounds of the invention containing a heterocyclic group wherein the hetero atom is a nitrogen atom may be oxidised to their corresponding N-oxides. The oxidation may conveniently be carried out by means of reaction with a mixture of hydrogen peroxide and an organic acid, e.g. acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90xc2x0 C. Alternatively, the oxidation may be carried out by reaction with a peracid, for example peracetic acid or m-chloroperoxybenzoic acid, in an inert solvent such as chloroform or dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature. The oxidation may alternatively be carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60xc2x0 C.
It will be appreciated that compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. IBM It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.
According to a further feature of the invention, acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
Compounds of this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
According to a further feature of the invention, base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
Acids of formula (II) wherein Het is 
(in which R13 is as hereinbefore defined), R1 and R3 are as hereinbefore defined, Z1 is NH and X1 is hydroxy may be prepared by reaction of compounds of formula (XIX): 
wherein R3 and R13 are as hereinbefore defined, R10 is lower alkyl and X is O, with isocyanates of formula R1xe2x80x94Nxe2x95x90Cxe2x95x90O in ethanol and at room temperature, followed by reaction with a carbodiimide, such as dicyclohexylcarbodiimide or diisopropylcarbodimide in ethanol and at a temperature from about room temperature to about reflux temperature, and subsequent hydrolysis using standard conditions, for example those described hereinbefore.
Compounds of general formula (XIX) wherein R13 is as hereinbefore defined, R3 is an alkylene chain, X is O, and R10 is lower alkyl may be prepared by the reduction of compounds of general formula (XX): 
wherein R13 and R3 are as hereinbefore defined, X is O, and R10 is lower alkyl. The reduction may be carried out using standard methods, such as those described hereinbefore, for example hydrogenation in the presence of palladium. This method is particularly suitable for the preparation of compounds of formula (XIX) where R3 is methylene and R13 is lower alkoxy.
Compounds of general formula (XX) wherein R3 and R13 are as hereinbefore defined, X is O and R10 is lower alkyl may be prepared by esterification of compounds of formula (XXI): 
wherein R3 and R13 are as hereinbefore defined and X is O using standard methods as described hereinbefore, for example reaction with a lower alkyl alcohol (e.g. methanol) in the presence of a mineral acid, e.g. concentrated sulphuric acid.
Compounds of formula (XX) wherein R3, R10 and R13 are as hereinbefore defined and X is O may also be prepared by reaction of compounds of formula (XXII): 
wherein R3, R10 and R13 are as hereinbefore defined and R14 is a suitable protecting group, such as alkyl- or arylcarbonyl, with a base, such as lithium hydroxide at a temperature at about room temperature. This method is particularly suitable for the preparation of compounds of formula (XX) where R3 is methylene, R13 is lower alkyl and R10 is tertiary butyl.
Compounds of general formula (XXI) wherein R3 and R13 are as hereinbefore defined and X is O may be prepared by reaction of compounds of general formula (XXIII): 
wherein R3 and R13 are as hereinbefore defined by reaction with pyridine hydrochloride at a temperature at about room temperature.
Compounds of formula (XXII) wherein R3, R10 are as hereinbefore defined, R13 is a lower alkyl group attached to the ring position adjacent to the nitro group and R14 is a suitable protecting group, such as alkyl- or arylcarbonyl, may be prepared by reaction of compounds of formula (XXIV): 
wherein R3, R10 are as hereinbefore defined and R14 is a suitable protecting group, such as alkyl- or arylcarbonyl, with a lower alkyl magnesium halide, such as methyl magnesium chloride, in an inert solvent, such as tetrahydrofuran, and at a temperature at about xe2x88x9215xc2x0 C.
Compounds of general formula (XXIII) wherein R3 is as hereinbefore defined and R13 is a methoxy group which is attached at the ring position adjacent to the nitro group, may be prepared by the treatment of compounds of general formula (XXV): 
wherein R3 and R10 are as hereinbefore defined with sodium methoxide, followed by hydrolysis of the ester using standard conditions for example those described hereinbefore.
Acids of formula (II) wherein Het is 
R1, R3 and R13 are as hereinbefore defined,
Z1 is NH and X1 is hydroxy may be similarly prepared from compounds of formula (XIX) wherein R3, R10 and R13 are as hereinbefore defined and X is NH.
Acid chlorides of formula (II) wherein Het, R1, R3 and Z1 are as hereinbefore defined and X1 is a chlorine atom may be prepared from the corresponding acids of formula (II) wherein Het, R1, R3 and Z1 are as hereinbefore defined and X1 is hydroxy, by the application of standard procedures for the conversion of acids to acid chlorides for example by reaction with oxalyl chloride.
Compounds of formula (III) wherein R2, R10 and L2 are as hereinbefore defined and R5 is hydrogen may be prepared by reduction of the corresponding nitro compounds. The reduction may be carried IS out using iron powder and ammonium chloride, in aqueous ethanol at a temperature at about reflux. The reduction may also be carried out by hydrogenation using standard conditions, for example those described hereinbefore.
Compounds of formula (XIX) wherein R3, R10 and R13 are as hereinbefore defined and X is NH may be similarly prepared by reduction of the corresponding nitro-amino compounds or dinitro compounds.
Compounds of formula (IV) wherein Het, R1, R3 and Z1 are as hereinbefore defined and R5 is hydrogen may be prepared by reaction of compounds of formula (VII) wherein Het, R1, R3 and Z1 are as hereinbefore defined and X3 is bromo with phthalimide potassium salt in dimethylformamide followed by reaction with hydrazine hydrate in ethanol (for example using the conditions described by O. Diouf et al., Heterocycles, 1995, 41, page 1219-1233) .
Compounds of formula (IV) wherein Het, R1, R3 and Z1 are as hereinbefore defined and R5 is methyl may be prepared by treatment of the corresponding compounds of formula (IV) wherein Het, R1, R3 and Z1 are as hereinbefore defined and R5 is hydrogen with formic acetic anhydride followed by reduction with lithium aluminium hydride according to the procedure described by L. G. Humber et al, J. Med. Chem., 1971, 14, page 982.
Compounds of formula (VI) wherein Het, R1 and Z1 are as hereinbefore defined and R3 is methylene, may be prepared by reduction of esters of formula (XXVI):
R1Z1xe2x80x94Hetxe2x80x94R12CO2R10xe2x80x83xe2x80x83(XXVI)
wherein Het, R1 and Z1 are as hereinbefore defined, R10 is alkyl and R12 is a direct bond. The reduction may conveniently be carried out with diisobutylaluminium hydride in an inert solvent, such as tetrahydrofuran, at a temperature from about xe2x88x9278xc2x0 C. to about room temperature. The reduction may also be carried out with lithium aluminium hydride in an inert solvent, such as an ether, for example diethyl ether, at a temperature from about room temperature to about reflux.
Compounds of formula (VI) in which R3 is a straight chain alkylene other than methylene may be similarly prepared esters of formula (XX) in which R12 is the appropriate alkylene chain containing one carbon atom less than the alkylene chain in R3 as just defined.
Compounds of formula (VIII) wherein Het, R1 and Z1 are as hereinbefore defined, R3 is an alkylene chain and X3 is bromo may be prepared by reaction of compounds of formula (VI) wherein Het, R1 and Z1 are as hereinbefore defined, R3 is an alkylene chain with phosphorus tribromide in an inert solvent such as carbon tetrachloride and at a temperature at about room temperature.
Esters of formula (IX) wherein Het, R1, R3 and Z1 are as hereinbefore defined and R10 is lower alkyl may be prepared from the corresponding acids of formula (II) by standard esterification procedures for example reaction with a lower alkyl alcohol (e.g. methanol) in the presence of an acid catalyst, such as hydrogen chloride or sulphuric acid.
Esters of formula (XXVI) wherein Het, R1, R12 and Z1 are as hereinbefore defined and R10 is alkyl may be similarly prepared from the corresponding acids.
Compounds of formula (X) wherein R2, R10 and L2 are as hereinbefore defined may be prepared from bromo-iodobenzene by the adaptation of procedures described by Y. Tamaru et al, Tetrahedron Letters, 1985, 26, page 5559 and 1986, 27, page 955.
Compounds of formula (X1) wherein Het, R1, R3 and Z1 are as hereinbefore defined may be prepared from compounds of formula (IV) wherein Het, R1, R3 and Z1 are as hereinbefore defined and R5 is hydrogen with phosgene following standard reaction conditions for the conversion of amines to isocyanates.
Compounds of formula (XIII) wherein Het, R1, R3 and Z1 are as hereinbefore defined may be prepared by reaction of compounds of formula (VIII) wherein Het, R1, R3 and Z1 are as hereinbefore defined and X3 is a bromine atom with sodium sulphite then with phosphorus trichloride according to the procedure described by P. N. Culshaw and J. C. Walton, J. Chem. Soc., Perkin Trans II, 1991, 8, page 1201-1208.
Compounds of formula (XVI) wherein Het, R1 and Z1 are as hereinbefore defined, R3 is a straight or branched chain C1-5alkylene chain and X5 is xe2x95x90PPh3+Brxe2x88x92 may be prepared by reaction of compounds of formula (VIII) wherein Het, R1, R3 and Z1 are as hereinbefore defined and X3 is a bromine atom by reaction with triphenylphosphine in an inert solvent and at a temperature from about room temperature to about reflux temperature of the solvent.
The present invention is further Exemplified but not limited by the following illustrative Examples and Reference Examples.
High Pressure Liquid Chromatography/Mass Spectrometry (LC-MS) conditions for determination of retention times (RT) were as follows: 3 micron Luna C18 (2) HPLC column (30 mmxc3x974.6 mm) operated under gradient elution conditions with mixtures of (A) water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid as the mobile phase gradient: 0.00 minutes, 95% A:5% B; 0.50 minutes, 95% A:5% B; 4.50 minutes, 5% A:95% B; 5.00 minutes, 5% A:95% B; 5.50 minutes, 95% A:5% B; flow rate 2 ml/minute with approximately 200 xcexcl/minute split to the Mass Spectrometer; injection volume 10-40 xcexcl; in line Diode Array (220-450 nm), in line Evaporative light scattering (ELS) detection ELSxe2x80x94temperature 50xc2x0 C., Gain 8xe2x80x941.8 ml/minute; Source temperature 150xc2x0 C.
Accurate Mass spectra were recorded on a Brucker 3T Ion cylclotrom mass spectrometer.